Studying Pathogenic Mechanism of Hereditary Cerebral Amyloid Angiopathy

许多阿尔茨海默病（AD）患者患有改变的脑血流和受损的大脑皮层。 脉管系统此外，大多数痴呆患者同时存在AD和血管病变。 因此，循环缺陷可能在这种疾病中发挥重要作用。脑淀粉样血管病 (CAA)Aβ沉积在脑血管周围，是AD血管功能障碍的主要原因 并且在超过80%的AD患者中观察到。病人死后脑部病理检查 CAA表现为血管周围微出血、微梗死和毛细血管闭塞。然而，分子 CAA形成和CAA诱导的脑血管病变的机制尚不清楚。另外还有按 CAA的明确诊断需要尸检，因为CAA没有明确的生物标志物。 有罕见的熟悉形式的CAA，称为遗传性脑淀粉样血管病（HCAA），其中患者 显示夸大的CAA病理和严重的中风临床过程，以及患有早期 出现神经功能障碍痴呆最终死亡大多数HCAA的发生与 β-淀粉样前体蛋白（APP）基因内有突变。虽然大多数APP突变 总Aβ产生或促进毒性更大的Aβ42的形成，A β 42是与HCAA相关的突变的子集 导致血管中Aβ沉积增加。由于患有HCAA突变的患者具有严重的 脑血管缺陷沿着大量CAA，HCAA是检查致病因素的理想疾病 CAA的机制。 越来越多的证据表明，纤维蛋白原，血凝块的主要成分， AD的脑血管风险。纤维蛋白原以高亲和力与Aβ结合，这种相互作用增加了A β的表达。 异常纤维蛋白凝块、CAA、炎症和脑血管损伤的发生率。我们的初步结果 表明HCAA突变高度增加了Aβ与纤维蛋白原结合亲和力， 与野生型（WT）Aβ相比，改变了纤维蛋白凝块结构。基于这些发现，我们假设HCAA 突变增加了Aβ与纤维蛋白原的结合亲和力，随后诱导更严重的纤维蛋白改变 凝血，增加血管纤维蛋白和Aβ沉积，并加剧炎症和脑血管疾病 损害通过在HCAA小鼠模型中研究我们的假设，以及死前CSF和 我们的目标是了解HCAA患者死后的脑组织的分子机制 HCAA中CAA和脑血管异常增加。如果我们的实验成功， 结果将有助于我们更好地了解CAA血管贡献的致病机制 在AD和HCAA患者中。此外，我们的研究将为CAA提供新的CSF生物标志物。 此外，这些发现可能会加速发现血管性痴呆的易处理的治疗方法。 AD的病理学

Many Alzheimer's disease (AD) patients suffer from altered cerebral blood flow and a damaged cerebral vasculature. Moreover, the majority of patients with dementia present with both AD and vascular pathologies. Circulatory deficiencies could therefore play an important role in this disease. Cerebral amyloid angiopathy (CAA), where Aβ deposits around cerebral blood vessels, is a major contributor of vascular dysfunction in AD and is observed in more than 80% of AD patients. Post-mortem pathological examination of patients' brains with CAA shows perivascular microhemorrhage, microinfarcts, and capillary occlusion. However, the molecular mechanism underlying CAA formation and CAA-induced cerebrovascular pathology is unclear. In addition, a definitive diagnosis of CAA requires autopsy as there is no clear biomarker for CAA. There are rare familiar forms of CAA, called hereditary cerebral amyloid angiopathy (HCAA), in which patients display exaggerated CAA pathology and a severe clinical course of strokes as well as suffering from early onset neurological dysfunction, dementia, and ultimately death. The majority of HCAA occurrences coincide with mutations within the gene for the β-amyloid precursor protein (APP). While most APP mutations elevate total Aβ production or promote formation of the more toxic Aβ42, a subset of mutations related to HCAA causes an increase in vascular deposits of Aβ. Since patients afflicted by HCAA mutations have severe cerebrovascular deficits along with massive CAA, HCAA is an ideal disease to examine the pathogenic mechanisms of CAA. Increasing evidence suggests that fibrinogen, a major component of blood clots, contributes heavily to the cerebrovascular risk in AD. Fibrinogen binds to Aβ with high affinity, and this interaction increases the incidence of abnormal fibrin clots, CAA, inflammation, and cerebrovascular damage. Our preliminary results indicate that HCAA mutations highly increase Aβ’s binding affinity for fibrinogen and induce more severely altered fibrin clot structure than wild-type (WT) Aβ. Based on these findings, we hypothesize that HCAA mutations increase Aβ’s binding affinity for fibrinogen, which subsequently induces more severely altered fibrin clotting, increases vascular fibrin and Aβ deposition, and exacerbates inflammation and cerebrovascular damage. By investigating our hypothesis in a mouse model of HCAA, as well as antemortem CSF and postmortem brain tissue of HCAA patients, we aim to understand the molecular mechanism underlying increased CAA and cerebrovascular abnormalities in HCAA. If our proposed experiments are successful, the results will help us to better understand the pathogenic mechanism underlying the vascular contribution of CAA in both AD and HCAA patients. In addition, our research will provide a novel CSF biomarker for CAA. Furthermore, these findings may accelerate the discovery of tractable therapeutic methods for vascular pathology in AD.